Department of Medicine, Columbia University Irving Medical Center, New York, New York.
Now with Winship Cancer Institute at Emory University, Atlanta, Georgia.
JAMA Oncol. 2021 Feb 1;7(2):271-278. doi: 10.1001/jamaoncol.2020.6741.
In the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, agents targeting genetic tumor abnormalities are administered to patients. In the NCI-MATCH subprotocol EAY131-Y trial, patients with an AKT1 E17K-mutated metastatic tumor received the pan-AKT inhibitor capivasertib.
To assess the objective response rate (ORR) of capivasertib in patients with an AKT1 E17K-mutated tumor.
DESIGN, SETTING, AND PARTICIPANTS: Between July 13, 2016, and August 10, 2017, patients in the NCI-MATCH trial were enrolled and assigned to the subprotocol EAY131-Y nonrandomized trial. Patients included adults with an AKT1 E17K-mutated metastatic tumor that had progressed with standard treatment, and these patients were assigned to receive capivasertib. Tumor assessments were repeated every 2 cycles. Data analysis of this evaluable population was performed from November 8, 2019, to March 12, 2020.
The study treatment was capivasertib, 480 mg, orally twice daily for 4 days on and 3 days off weekly in 28-day cycles until disease progression or unacceptable toxic effect. If patients continued hormone therapy for metastatic breast cancer, the capivasertib dose was 400 mg.
The primary end point was the ORR (ie, complete response [CR] and partial response) according to the Response Evaluation Criteria in Solid Tumors criteria, version 1.1. Secondary end points included progression-free survival (PFS), 6-month PFS, overall survival, and safety.
In total, 35 evaluable and analyzable patients were included, of whom 30 were women (86%), and the median (range) age was 61 (32-73) years. The most prevalent cancers were breast (18 [51%]), including 15 patients with hormone receptor (HR)-positive/ERBB2-negative and 3 with triple-negative disease, and gynecologic (11 [31%]) cancers. The ORR rate was 28.6% (95% CI, 15%-46%). One patient with endometrioid endometrial adenocarcinoma achieved a CR and remained on therapy at 35.6 months. Patients with confirmed partial response had the following tumor types: 7 had HR-positive/ERBB2-negative breast cancer, 1 had uterine leiomyosarcoma, and 1 had oncocytic parotid gland carcinoma and continued receiving treatment at 28.8 months. Sixteen patients (46%) had stable disease as the best response, 2 (6%) had progressive disease, and 7 (20%) were not evaluable. With a median follow-up of 28.4 months, the overall 6-month PFS rate was 50% (95% CI, 35%-71%). Capivasertib was discontinued because of adverse events in 11 of 35 patients (31%). Grade 3 treatment-related adverse events included hyperglycemia (8 [23%]) and rash (4 [11%]). One grade 4 hyperglycemic adverse event was reported.
This nonrandomized trial found that, in patients with an AKT1 E17K-mutated tumor treated with capivasertib, a clinically significant ORR was achieved, including 1 CR. Clinically meaningful activity with single-agent capivasertib was demonstrated in refractory malignant neoplasms, including rare cancers.
ClinicalTrials.gov Identifier: NCT00700882.
在国家癌症研究所分子分析用于治疗选择（NCI-MATCH）试验中，靶向遗传肿瘤异常的药物被给予患者。在 NCI-MATCH 子协议 EAY131-Y 试验中，具有 AKT1 E17K 突变转移性肿瘤的患者接受了泛 AKT 抑制剂 capivasertib 的治疗。
评估 AKT1 E17K 突变肿瘤患者接受 capivasertib 的客观缓解率（ORR）。
设计、地点和参与者：2016 年 7 月 13 日至 2017 年 8 月 10 日期间，NCI-MATCH 试验中的患者被招募并被分配到非随机子协议 EAY131-Y 试验中。患者包括标准治疗后进展的具有 AKT1 E17K 突变的转移性肿瘤的成年人，这些患者被分配接受 capivasertib 治疗。每 2 个周期重复肿瘤评估。从 2019 年 11 月 8 日至 2020 年 3 月 12 日，对可评估人群进行数据分析。
研究治疗是 capivasertib，480mg，口服，每日两次，连续 4 天，然后停药 3 天，每 28 天为一个周期，直到疾病进展或不可接受的毒性作用。如果患者继续接受转移性乳腺癌的激素治疗，则 capivasertib 的剂量为 400mg。
主要终点是 ORR（即完全缓解[CR]和部分缓解），根据实体瘤反应评估标准，版本 1.1。次要终点包括无进展生存期（PFS）、6 个月 PFS、总生存期和安全性。
共纳入 35 名可评估和可分析的患者，其中 30 名为女性（86%），中位（范围）年龄为 61（32-73）岁。最常见的癌症是乳腺癌（18 例[51%]），包括 15 例激素受体（HR）阳性/ERBB2 阴性和 3 例三阴性疾病，以及妇科（11 例[31%]）癌症。ORR 率为 28.6%（95%CI，15%-46%）。1 例子宫内膜样腺癌患者获得 CR，在 35.6 个月时仍在接受治疗。确认部分缓解的患者的肿瘤类型如下：7 例 HR 阳性/ERBB2 阴性乳腺癌、1 例子宫平滑肌肉瘤、1 例嗜酸细胞性腮腺癌，在 28.8 个月时仍在接受治疗。16 例（46%）患者的最佳反应为疾病稳定，2 例（6%）患者疾病进展，7 例（20%）患者无法评估。中位随访 28.4 个月时，总体 6 个月 PFS 率为 50%（95%CI，35%-71%）。由于不良事件，35 例患者中的 11 例（31%）停止了 capivasertib 的治疗。3 级与治疗相关的不良事件包括高血糖（8[23%]）和皮疹（4[11%]）。报告了 1 例 4 级高血糖不良事件。
这项非随机试验发现，在接受 capivasertib 治疗的 AKT1 E17K 突变肿瘤患者中，达到了有临床意义的 ORR，包括 1 例 CR。在难治性恶性肿瘤中，包括罕见癌症，单药 capivasertib 表现出了有临床意义的活性。
ClinicalTrials.gov 标识符：NCT00700882。
